Doxepin trans isomers and isomeric mixtures and methods of using the same to treat sleep disorders

ABSTRACT

The invention relates to use of the trans-(E) isomer or isomeric mixtures containing specified ratios of the trans-(E) and cis-(Z) isomers of doxepin, metabolites of doxepin, pharmaceutically-acceptable salts of doxepin and prodrugs of the same; compositions containing the same, for the treatment of sleep disorders.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/357,171, filed Nov. 21, 2016, which is a continuation of U.S.application Ser. No. 13/692,715, filed Dec. 3, 2012, now U.S. Pat. No.9,498,462, which is a continuation of U.S. application Ser. No.12/535,623, filed Aug. 4, 2009, now abandoned, which is acontinuation-in-part of U.S. application Ser. No. 12/022,788, filed Jan.30, 2008, now abandoned, which claims the benefit of, and priority to,U.S. Provisional Application No. 60/898,378, filed Jan. 30, 2007; andU.S. application Ser. No. 12/022,788 is a continuation-in-part of U.S.application Ser. No. 11/804,720, filed May 18, 2007, now U.S. Pat. No.8,513,299, which claims priority to U.S. Provisional Application Nos.60/801,824, filed May 19, 2006, and 60/833,319, filed July 25, 2006. Theentire content of all of these applications are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Field of the Invention

The invention relates to use of the trans-(E) isomer or isomericmixtures containing specified ratios of the trans-(E) and cis-(Z)isomers of doxepin and metabolites of doxepin, as well aspharmaceutically-acceptable salts and prodrugs of the same; andcompositions containing the same, for the treatment of sleep disorders.

Description of the Related Art

Sleep is essential for health and quality of life. Insomnia is asubjective complaint of dissatisfaction with the quantity, quality ortiming of sleep. Insomnia is estimated to occur in approximately 12% to25% of the general population, although this is probably anunderestimate as there is evidence that many adults do not report theirsleep problems to a health care professional.

One study has found that fewer than 15% of those who suffer frominsomnia are treated with prescription medications. Medications commonlyused to treat sleep disorders such as insomnia, include sedativeantidepressants, antipsychotics, antihistamines, melatonin receptoragonists, benzodiazepines, and non-benzodiazepine hypnotics.

Benzodiazepines work by binding to and activating sites on the GABA-Areceptor complex. Short, intermediate and long-acting benzodiazepinessuch as triazolam, temazepam and flurazepam were all commonly prescribedfor this indication. While these agents have proven to be efficaciousand relatively safe, benzodiazepines are associated with a multitude ofadverse effects, including residual daytime sedation (“hangover”),amnesia, memory loss and respiratory depression. Rebound insomnia hasalso been associated with benzodiazepines. Tolerance to the hypnoticeffects of the benzodiazepines is common and abrupt discontinuation canresult in withdrawal symptoms such as agitation, rebound insomnia,perceptual changes, confusion, disorientation and even seizures.

Non-benzodiazepine hypnotics have become the primary class ofmedications for the treatment of insomnia. The leading approvednon-benzodiazepine insomnia medications, eszopiclone, zolpidem, andzaleplon, also work by binding to and activating the GABA-A receptors.All these drugs approved for the treatment of insomnia that act via theGABA-A receptor, including benzodiazepine and non-benzodiazepinehypnotics, have a potential for addiction and abuse and are classifiedas Schedule IV controlled substances by the U.S. Drug EnforcementAdministration. As a result, many physicians are reluctant to prescribe,and patients are reluctant to take these drugs for chronic use intreating insomnia. The prescribing of a Schedule IV controlled substancebrings scrutiny from the Drug Enforcement Administration and otherregulatory bodies, and requires registration and administrative controlsin physicians' offices.

Also, the sedative antidepressants account for a large percentage of thetotal prescriptions written for insomnia. The National Disease andTherapeutic Index estimates that more than 60% of the 13 million annualtrazodone prescriptions are written for the treatment of insomnia, eventhough trazodone is not indicated for that usage and has never beenpromoted for that condition. Although there are very limited data tosupport the use of trazodone for insomnia and it is associated withundesirable side effects, trazodone is often prescribed because it is anon-scheduled agent, meaning non-addictive, unlike the benzodiazepinesand other GABA-receptor agonists which are approved for the treatment ofinsomnia.

Recently a new hypnotic with a mode of action different from otherhypnotics has been introduced. Ramelteon is a melatonin receptor agonistwith high affinity for melatonin MT1 and MT2 receptors. It is indicatedfor sleep onset insomnia but it has not been shown to produce a sleepmaintenance benefit. It does not affect the GABA-A receptor complex, isnot addicting and is not scheduled.

Therefore, it is desirable to have a pharmacological agent for thetreatment of insomnia which is more effective and/or has fewer sideeffects that those currently used.

SUMMARY OF THE INVENTION

In some embodiments, the present invention relates to a method for thetreatment of a patient suffering from insomnia including administeringto the patient doxepin, a pharmaceutically-acceptable salt or a prodrugthereof in a daily dosage ranging from about 0.0001 to about 499milligrams, wherein the doxepin, the salt or the prodrug is a geometricisomer mixture containing about 88.3% to about 100.0% of the trans-(E)isomer or is 100% trans-(E) isomer. In some embodiments, the presentinvention relates to a method for treating insomnia characterized bydifficulties with sleep maintenance, the method comprising administeringa dosage of doxepin or a pharmaceutically acceptable salt thereof to apatient having a sleep disorder in which, for a given 8 hour period ofdesired sleep, the patient experiences fragmented sleep during the final60 minutes of said period, wherein the dosage of doxepin is betweenabout 1 and about 6 mg, wherein the doxepin or salt thereof is ageometric isomer mixture containing about 88.3% to about 100.0% of thetrans-(E) isomer or is 100% trans-(E) isomer, and wherein the dosage isadministered prior to the start of the sleep period. In someembodiments, the present invention relates to a method for treatinginsomnia characterized by difficulties with sleep maintenance, themethod comprising administering a dosage of doxepin or apharmaceutically acceptable salt thereof to a patient having a sleepdisorder in which, for a given 8 hour period of desired sleep, thepatient experiences early awakenings during the final 60 minutes of saidperiod, wherein the dosage of doxepin is between about 1 and about 6 mg,wherein the doxepin or salt thereof is a geometric isomer mixturecontaining about 88.3% to about 100.0% of the trans-(E) isomer or is100% trans-(E) isomer, and wherein the dosage is administered prior tothe start of the sleep period. The geometric isomer mixture can, in someembodiments, contain more than 90%, 95%, 98%, or 99% of the trans-(E)isomer. The geometric isomer mixture may contain at least 99.5% or 99.9%of the trans-(E) isomer. In some embodiments, the geometric isomermixture contains 100.0% of the trans-(E) isomer. The geometric isomermixture may contain about 89% to about 99.9% of the trans-(E) isomer,about 90% to about 99.5% of the trans-(E) isomer, about 95% to about 99%of the trans-(E) isomer, about 89% to about 97% of the trans-(E) isomer,or about 89% to about 94.9% of the trans-(E) isomer.

The pharmaceutically-acceptable salt of doxepin may be the hydrochloridesalt thereof. The prodrug of doxepin may be a prodrug ester.

In some embodiments, the daily dosage is about 0.0001 to about 249milligrams, about 0.001 to about 99 milligrams, about 0.001 to about 49milligrams, about 0.001 to about 24 milligrams, about 20 to about 49milligrams, about 0.01 to about 24 milligrams, about 0.01 to about 20milligrams, about 0.01 to about 10 milligrams, or about 0.1 to about 5milligrams.

The insomnia may be a chronic insomnia or a non-chronic insomnia. Thenon-chronic insomnia may be a transient or a short-term insomnia. Theinsomnia may be selected from the group consisting of onset insomnia andmaintenance insomnia.

In some embodiments, the patient is not suffering from depression. Inother embodiments, the patient is suffering from depression.

A method disclosed herein can further include administering at least oneof ramelteon, VEC-162, gaboxadol, APD125, trazodone, indiplon, AVE 8488,MDL 100907, AVE 8488, MDL 100907, eszopiclone, zolpidem, tiagabine,ketanserin, and zaleplon. In some embodiments, a method disclosed hereincan further include administering at least one additional medication.The at least one additional medication may be selected from a 5-HT2antagonist, a H3 agonist, an orexin antagonist, a noradrenergicantagonist, a galanin agonist, a CRH antagonist, a GABA-A directagonist, a GABA reuptake inhibitor, a growth hormone, a growth hormoneagonist, estrogen, an estrogen agonist, an ion channel blocker, and amelatonin agonist.

In some embodiments, the present invention relates to a compositionincluding a pharmaceutically-acceptable carrier and doxepin, apharmaceutically-acceptable salt of doxepin, or a prodrug of doxepin ina unit dosage form of about 0.0001 milligrams to about 499 milligrams,wherein the doxepin, the salt or the prodrug is a geometric isomermixture containing about 88.3% to about 100.0% of the trans-(E) isomeror is 100% trans-(E) isomer. The geometric isomer mixture can, in someembodiments, contain more than 90%, 95%, 98%, or 99% of the trans-(E)isomer. The geometric isomer mixture may contain at least 99.5% or 99.9%of the trans-(E) isomer. In some embodiments, the geometric isomermixture contains 100.0% of the trans-(E) isomer. The geometric isomermixture may contain about 89% to about 99.9% of the trans-(E) isomer,about 90% to about 99.5% of the trans-(E) isomer, about 95% to about 99%of the trans-(E) isomer, about 89% to about 97% of the trans-(E) isomer,or about 89% to about 94.9% of the trans-(E) isomer.

The pharmaceutically-acceptable salt of doxepin may be the hydrochloridesalt thereof. The prodrug may be an ester.

The unit dosage can, in some embodiments, be about 0.0001 to about 249milligrams, about 0.001 to about 99 milligrams, about 0.001 to about 49milligrams, about 0.001 to about 24 milligrams, about 0.1 to about 24milligrams, about 0.1 to about 20 milligrams, about 0.1 to about 10milligrams, or about 0.1 to about 5 milligrams.

The composition may be formulated for oral or nasal administration. Theunit dosage form may be selected from the group consisting of a pill, atablet, a capsule, a gel cap, and a fast melt formulation.

In some embodiments, the present invention relates to a method fortreating insomnia including administering to a patient a metabolite ofdoxepin, a pharmaceutically-acceptable salt thereof, or a prodrugthereof in a dosage ranging from about 0.0001 to about 499 milligrams,wherein the metabolite of doxepin, the salt or the prodrug is ageometric isomer mixture containing about 88.3% to about 100.0% of thetrans-(E) isomer or is 100% trans-(E) isomer. The geometric isomermixture can, in some embodiments, contain more than 90%, 95%, 98%, or99% of the trans-(E) isomer of the metabolite. The geometric isomermixture may contain at least 99.5% or 99.9% of the trans-(E) isomer ofthe metabolite. In some embodiments, the geometric isomer mixturecontains 100.0% of the trans-(E) isomer of the metabolite. The geometricisomer mixture may contain about 89% to about 99.9% of the trans-(E)isomer of the metabolite, about 90% to about 99.5% of the trans-(E)isomer of the metabolite, about 95% to about 99% of the trans-(E) isomerof the metabolite, about 89% to about 97% of the trans-(E) isomer of themetabolite, or about 89% to about 94.9% of the trans-(E) isomer of themetabolite.

The metabolite of doxepin, the pharmaceutically-acceptable salt, or theprodrug may be administered in a dosage ranging from about 0.0001 toabout 249 milligrams, about 0.001 to about 99 milligrams, about 0.001 toabout 49 milligrams, or about 0.01 to about 24 milligrams.

The insomnia may be a chronic or a non-chronic insomnia. The non-chronicinsomnia may be a transient or a short-term insomnia. The insomnia maybe selected from the group consisting of onset insomnia and maintenanceinsomnia. The metabolite can be, in some embodiments, desmethyldoxepin,hydroxydoxepin, hydroxyl-N-desmethyldoxepin, or doxepin N-oxide.

In some embodiments, a method disclosed herein can further includeadministering at least one of ramelteon, VEC-162, gaboxadol, APD125,trazodone, indiplon, AVE 8488, MDL 100907, AVE 8488, MDL 100907,eszopiclone, zolpidem, tiagabine, ketanserin and zaleplon. In someembodiments, a method disclosed herein can further include administeringat least one additional medication. In some embodiments, a methoddisclosed herein can further include administering at least oneadditional sleep medication. The at least one additional sleepmedication may be selected from a 5-HT2 antagonist, a H3 agonist, anorexin antagonist, a noradrenergic antagonist, a galanin agonist, a CRHantagonist, a GABA-A direct agonist, a GABA reuptake inhibitor, a growthhormone, a growth hormone agonist, estrogen, an estrogen agonist, an ionchannel blocker, and a melatonin agonist. In some embodiments, the 5-HT2antagonist is selected from ketanserin, risperidone, eplivanserin,pruvanserin, MDL 100907, APD125, and AVE 8488. The ion channel block maybe one selected from lamotrigine, gabapentin, and pregabalin. In someembodiments, the melatonin agonist is one selected from melatonin,ramelteon, and agomelatine. The at least one additional sleep medicationmay be selected from clobazam, clonazepam, clorazepate, diazepam,flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam,temazepam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon,zolpidem, gaboxadol, vigabatrin, tiagabine and estazolam.

In some embodiments, the present invention relates to a compositionincluding a pharmaceutically-acceptable carrier and a metabolite ofdoxepin, a pharmaceutically-acceptable salt of the metabolite, or aprodrug of the metabolite in unit dosage form of about 0.0001 milligramsto about 499 milligrams, wherein doxepin, the salt or the prodrug is ageometric isomer mixture containing about 88.3% to about 100.0% of thetrans-(E) isomer of the metabolite or is 100% trans-(E) isomer. Thegeometric isomer mixture can, in some embodiments, contain more than90%, 95%, 98%, or 99% of the trans-(E) isomer of the metabolite. Thegeometric isomer mixture may contain at least 99.5% or 99.9% of thetrans-(E) isomer of the metabolite. In some embodiments, the geometricisomer mixture contains 100.0% of the trans-(E) isomer of themetabolite. The geometric isomer mixture may contain about 89% to about99.9% of the trans-(E) isomer of the metabolite, about 90% to about99.5% of the trans-(E) isomer of the metabolite, about 95% to about 99%of the trans-(E) isomer of the metabolite, about 89% to about 97% of thetrans-(E) isomer of the metabolite, or about 89% to about 94.9% of thetrans-(E) isomer of the metabolite.

The pharmaceutically-acceptable salt of the metabolite may be thehydrochloride salt thereof. The prodrug may be an ester. The metabolitemay be desmethyldoxepin, hydroxydoxepin, hydroxyl-N-desmethyldoxepin, ordoxepin N-oxide.

The unit dosage can, in some embodiments, be about 0.0001 to about 249milligrams, about 0.001 to about 99 milligrams, about 0.001 to about 49milligrams, about 0.001 to about 24 milligrams, about 0.1 to about 24milligrams, about 0.1 to about 20 milligrams, about 0.1 to about 10milligrams, or about 0.1 to about 5 milligrams.

The composition may be formulated for oral or nasal administration. Theunit dosage form may be selected from the group consisting of a pill, atablet, a capsule, a gel cap, and a fast melt formulation.

In some embodiments, the present invention relates to a method for thetreatment of a patient suffering from insomnia including providing acomposition enriched in trans isomer compared to the ratio of thetrans-/cis-isomers in doxepin as typically prepared, a metabolite ofdoxepin, a salt of doxepin, a salt of a metabolite of doxepin, a prodrugof doxepin, or a prodrug of a metabolite of doxepin, andadministering/prescribing to the patient the enriched composition oftrans isomer of doxepin, a metabolite of doxepin, a salt of doxepin, asalt of a metabolite of doxepin, a prodrug of doxepin, or a prodrug of ametabolite of doxepin.

In some embodiments, the present invention relates to a compositionincluding doxepin, a metabolite of doxepin, a salt of doxepin, a salt ofa metabolite of doxepin, a prodrug of doxepin, or a prodrug of ametabolite of doxepin, wherein the ratio of the trans/cis-isomers ismore than that found in the doxepin as typically prepared.

In some embodiments, the present invention relates to a method for thetreatment of a patient suffering from insomnia including providing acomposition enriched in trans isomer compared to ratio of thetrans-/cis-isomers in one or more of the following: a metabolite ofdoxepin, a salt of doxepin, a salt of a metabolite of doxepin, a prodrugof doxepin, or a prodrug of a metabolite of doxepin, comparing saidratio of the trans-/cis-isomers to the ratio of trans-/cis-isomers indoxepin as typically prepared, and administering/prescribing to thepatient the enriched composition of the trans isomer of the metaboliteof doxepin, salt of doxepin, salt of the metabolite of doxepin, prodrugof doxepin, or prodrug of the metabolite of doxepin.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Generally, embodiments of the present invention relate to doxepinisomers, doxepin metabolite isomers, including pharmaceuticallyacceptable salts and prodrugs of the same, as well as compositions ofthe same. In some aspects the isomers can be in a substantially pureform (e.g., at least 95%, 97%, 99%, 99.5%, 99.9% or 100% trans isomer).In other aspects the isomers can be in an isomeric mixture as describedherein. Also, embodiments relate to the use of the trans-(E) isomer orgeometric isomeric mixtures containing specified ratios of the trans-(E)to cis-(Z) isomers of doxepin or doxepin metabolites, prodrugs, or saltsof the same to treat an individual suffering from a sleep disorder, forexample a disorder such as insomnia. Several examples of insomnias thatcan be treated using the isomers and isomeric mixtures are describedbelow. In some embodiments, the sleep disorder, such as insomnia, can betreated by administering low dosages of doxepin or doxepin metaboliteisomers and isomeric mixtures, while in others it can be administered ina higher dosage. Various dosages of isomers are described below.Surprisingly, when used in specific isomeric ratios described herein,low doses of doxepin isomers and isomers of doxepin metabolites are veryeffective in treating insomnia with very minimal side effects. Theisomers and isomer mixtures, as well as their uses, as described hereinhave not been described previously, particularly for use in thetreatment of sleep disorders.

Doxepin is a tricyclic compound approved for the treatment of depressionand anxiety. The recommended daily dose for the treatment of depressionand anxiety ranges from 75 milligrams to 300 milligrams. Doxepin, unlikemost FDA approved products for the treatment of insomnia, is not aSchedule IV controlled substance.

U.S. Pat. Nos. 5,502,047 and 6,211,229, the entire contents of which areincorporated herein by reference, describe the use of doxepin for thetreatment of chronic and non-chronic (e.g., transient/short term)insomnias at dosages far below those used to treat depression.

No studies have investigated whether sleep disorders can be effectivelytreated by isomers or geometric isomeric mixtures of doxepin or doxepinmetabolites, pharmaceutically-acceptable salts or prodrugs of the same,for example, in mixtures containing higher proportions of the trans-(E)isomer than found in doxepin as typically prepared. According to USP 25,2002. United States Pharmacopeial Convention, Inc., Rockville, Md. P.615, doxepin hydrochloride U.S.P. is a geometric isomer mixture“containing not less than 13.6% and not more than 18.1%” of the cisisomer and “not less than 81.4% and not more than 88.2%” of the transisomer.

Methods of Treating Sleep Disorders

Some embodiments of the instant invention relate to methods for thetreatment of a patient suffering from a sleep disorder, such asinsomnia. The methods can include the administration to a patient of anisomer of doxepin, a mixture of doxepin isomers, an isomer of ametabolite of doxepin, a mixture of metabolite isomers, or apharmaceutically-acceptable salt or a prodrug of any of theaforementioned substances. The medication can be administered in anysuitable dosage to treat the sleep disorder, including the dosagesdescribed herein. For example, the medication can be administered in adaily dosage ranging from about 0.001, to about 9 milligrams, to about24 milligrams, to about 49 milligrams, to about 99 milligrams, to about249 milligrams, or to about 499 milligrams. Also, as previouslymentioned, the isomers can be administered alone (e.g, in asubstantially pure or pure form) or in an isomeric mixture. Examples ofisomeric ratios are described elsewhere herein. As an example, themedication can contain about 88.3% to about 100.0%, about 90% to about100.0%, about 95% to about 100.0%, about 98% to about 100.0%, about 99%to about 100.0%, about 99.5% to about 100.0%, about 99.9% to about100.0%, or 100.0% of the trans-(E) isomer. In some aspects asubstantially pure isomer can be administered, for example, at least95%, 97%, 98%, 99%, 99.5%, or 99.9% trans-(E) isomer. In some aspects apure or 100% trans-(E) isomer can be used in the methods. The insomniacan be any insomnia, including those described herein.

Some embodiments relate to methods for the treatment of a patientsuffering from insomnia, for example, by providing a compositionenriched in trans isomer compared to the ratio of the trans-/cis-isomersin doxepin as typically prepared, a metabolite of doxepin, a salt ofdoxepin, a salt of a metabolite of doxepin, a prodrug of doxepin, or aprodrug of a metabolite of doxepin; and administering/prescribing tosaid patient enriched composition of trans isomer of doxepin, ametabolite of doxepin, a salt of doxepin, a salt of a metabolite ofdoxepin, a prodrug of doxepin, or a prodrug of a metabolite of doxepin.“Native”, “native-occurring” or “as typically prepared” can refer, forexample, to a common form of the compound available in thepharmaceutical or chemical industry or a form produced by standardchemical synthesis.

Some embodiments relate to methods for the treatment of a patientsuffering from insomnia, for example, by providing a compositionenriched in trans isomer compared to ratio of the trans-/cis-isomers inone or more of the following: a metabolite of doxepin, a salt ofdoxepin, a salt of a metabolite of doxepin, a prodrug of doxepin, or aprodrug of a metabolite of doxepin; comparing the ratio of thetrans-/cis-isomers to the ratio of trans-/cis-isomers in doxepin astypically prepared; and administering/prescribing to said patient saidenriched composition of the trans isomer of the metabolite of doxepin,salt of doxepin, salt of the metabolite of doxepin, prodrug of doxepin,or prodrug of the metabolite of doxepin.

Also, some embodiments relate to compositions that include doxepin, ametabolite of doxepin, a salt of doxepin, a salt of a metabolite ofdoxepin, a prodrug of doxepin, or a prodrug of a metabolite of doxepin,wherein the ratio of the trans-/cis-isomers in the composition is morethan that found in the compound as typically prepared.

As mentioned above and elsewhere, the methods described herein can beused to treat individuals suffering from a sleep disorder, such asinsomnia. The term “insomnia” generally refers to sleep problemscharacterized by difficulty falling asleep, wakings during the night, orwaking up earlier than desired. Examples of insomnia include chronic andnon-chronic insomnias.

For chronic (e.g., greater than 3-4 weeks) or non-chronic insomnias, apatient may suffer from difficulties in sleep onset, sleep maintenance(interruption of sleep during the night by periods of wakefulness),sleep duration, sleep efficiency, premature early-morning awakening, ora combination thereof. Also, the insomnia may be attributable to theconcurrent use of other medication. The non-chronic insomnia can be, forexample, a short term insomnia or a transient insomnia. The chronic ornon-chronic insomnia can be a primary insomnia or an insomnia that issecondary or attributable to another condition, for example a disordersuch as depression or chronic fatigue syndrome. In some aspects, thepatient can be one who is not suffering from an insomnia that is acomponent of a disease, the patient can be one whose insomnia isunrelated to a disease, or a patient can be treated who is otherwisehealthy, for example. As previously mentioned, the chronic ornon-chronic insomnia can be a primary insomnia, that is, one that is notattributable to another disorder such as a mental or neurologicaldisorder, a general medical condition, or a substance. In many cases,such conditions may be associated with a chronic insomnia and caninclude, but are not limited to, insomnia attributable to a diagnosableDSM-IV disorder, a disorder such as anxiety or depression, or adisturbance of the physiological sleep-wake system. In some aspects theinsomnia can be non-chronic, or of short duration (e.g., less than 3-4weeks). Examples of causes of such insomnia may be extrinsic orintrinsic and include, but are not limited to environmental sleepdisorders as defined by the International Classification of SleepDisorders (ICSD) such as inadequate sleep hygiene, altitude insomnia oradjustment sleep disorder (e.g., bereavement). Also, short-term insomniamay also be caused by disturbances such as shift-work sleep disorder.

Also, some embodiments can include the use of an isomer of doxepin, amixture of doxepin isomers, an isomer of a metabolite of doxepin, amixture of metabolite isomers, or a pharmaceutically-acceptable salt ora prodrug of any of the aforementioned substances in combination withother insomnia or sleep medications. For example, the methods caninclude the use of one or more of ramelteon, VEC-162, APD125, trazodone,AVE 8488, MDL 100907, or the like. Further, the methods can include theuse of one or more of 5-HT2 antagonists (such as ketanserin), H3agonists, orexin antagonists, noradrenergic antagonists, galaninagonists and CRH antagonists. Similarly, the methods can use GABAmodulator (e.g., a compound that facilitates GABA neurotransmission)such as benzodiazepines, nonbenzodiazepine positive modulators such aseszopiclone, indiplon, zolpidem and zaleplon, GABA-A direct agonists(such as gaboxadol), and GABA reuptake inhibitor (such as tiagabine).Finally, the methods can use growth hormone and growth hormone agonists,estrogen and estrogen agonists, melatonin agonists or the like. Themethods can also include the use of one or more antihistamines.

An isomer of doxepin, a mixture of doxepin isomers, an isomer of ametabolite of doxepin, a mixture of metabolite isomers, or apharmaceutically-acceptable salt or a prodrug of any of theaforementioned substances may be used in combination with ramelteon.Ramelteon((S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide)can be used in any dosage, but preferably can be used in a dosage ofabout 0.5 milligrams to about 20 milligrams. More preferably, about 4, 8or 16 milligrams can be used, for example.

An isomer of doxepin, a mixture of doxepin isomers, an isomer of ametabolite of doxepin, a mixture of metabolite isomers, or apharmaceutically-acceptable salt or a prodrug of any of theaforementioned substances may be used in combination with eszopiclone.Eszopiclone also can be used in any suitable dosage. For example, thedosage can be about 0.1 to about 10 milligrams. Preferably, as anexample, the dosage can be about 1, 2, or 3 milligrams.

An isomer of doxepin, a mixture of doxepin isomers, an isomer of ametabolite of doxepin, a mixture of metabolite isomers, or apharmaceutically-acceptable salt or a prodrug of any of theaforementioned substances may be used in combination with zolpidem.Zolpidem (N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamideL-(+)-tartrate (2:1)) also can be used in any suitable dosage. Forexample, the dosage can be about 0.1 to about 20 milligrams. In someembodiments, as an example, the dosage can be about 6.25-milligrams,12.5 milligrams or a dosage that is a factor thereof. In otherembodiments, the dosage can be about 5-milligrams, 10-milligrams or adosage that is a factor thereof

Furthermore, an isomer of doxepin, a mixture of doxepin isomers, anisomer of a metabolite of doxepin, a mixture of metabolite isomers, or apharmaceutically-acceptable salt or a prodrug of any of theaforementioned substances may be used in combination with zaleplon.Zaleplon(N-[3-(3-cyantopryazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide)can be used in any suitable dosage. For example, the dosage can be about0.1 to about 20 milligrams. Preferably, as an example, the dosage can beabout 5, 10 or 20 milligrams, for example.

An isomer of doxepin, a mixture of doxepin isomers, an isomer of ametabolite of doxepin, a mixture of metabolite isomers, or apharmaceutically-acceptable salt or a prodrug of any of theaforementioned substances may be used in combination with gaboxadol.Gaboxadol (7-tetra hydroisoxazolo[5,4-c]pyridin-3-ol) can be used in anysuitable dosage. For example, the dosage can be about 0.1 to about 20 40milligrams. Preferably, as an example, the dosage can be about 0.5 toabout 20 milligrams or 10 or 15 milligrams, for example.

An isomer of doxepin, a mixture of doxepin isomers, an isomer of ametabolite of doxepin, a mixture of metabolite isomers, or apharmaceutically-acceptable salt or a prodrug of any of theaforementioned substances may be used in combination with VEC-162.VEC-162 can be used in any suitable dosage. For example, the dosage canbe about 0.1 to about 100 milligrams. Preferably, as an example, thedosage can be about 10, 20, 50 or 100 milligrams, for example.

An isomer of doxepin, a mixture of doxepin isomers, an isomer of ametabolite of doxepin, a mixture of metabolite isomers, or apharmaceutically-acceptable salt or a prodrug of any of theaforementioned substances may be used in combination with indiplon.Indiplon(N-methyl-N-[3-[3-(2-thienylcarbonyl)-pyrazolo[1,5-α]pyrimidin-7-yl]phenyl]acetamide)can be used in any suitable dosage. For example, the dosage can be about0.1 to about 10 milligrams. Preferably, as an example, the dosage can beabout 5 or 10 milligrams, for example.

An isomer of doxepin, a mixture of doxepin isomers, an isomer of ametabolite of doxepin, a mixture of metabolite isomers, or apharmaceutically-acceptable salt or a prodrug of any of theaforementioned substances may be used in combination with MDL 100907.MDL 100907 (Sanofi-Aventis) can be used in any suitable dosage. Forexample, the dosage can be about 0.5 to about 100 milligrams, orpreferably from about 1 to about 50 milligrams.

An isomer of doxepin, a mixture of doxepin isomers, an isomer of ametabolite of doxepin, a mixture of metabolite isomers, or apharmaceutically-acceptable salt or a prodrug of any of theaforementioned substances may be used in combination with APD125. APD125(Arena Pharmaceuticals) can be used in any suitable dosage. For example,the dosage can be about 1 to about 160 milligrams, preferably about 5 toabout 80 milligrams, or more preferably about 10 to about 40 milligrams.

An isomer of doxepin, a mixture of doxepin isomers, an isomer of ametabolite of doxepin, a mixture of metabolite isomers, or apharmaceutically-acceptable salt or a prodrug of any of theaforementioned substances may be used in combination with AVE8488. AVE8488 (Sanofi-Aventis) can be used in any suitable dosage. For example,the dosage can be about 0.5 to about 100 milligrams, or preferably fromabout 1 to about 50 milligrams. It should be noted that in some aspects,the methods can specifically exclude one or more of any of the sleepdisorders described in the previous paragraph or elsewhere herein. Forexample, without being limited thereto, in some aspects the methods canspecifically exclude treating a chronic insomnia. As another example,without being limited thereto, in some aspects the methods canspecifically exclude treating an insomnia that is attributable to acondition such as depression, anxiety or chronic fatigue.

Compounds of Doxepin and Metabolites

Doxepin:

Doxepin has the following structure:

For all compounds disclosed herein, unless otherwise indicated, where acarbon-carbon double bond is depicted, both the cis and transstereoisomers, as well as mixtures thereof are encompassed.

It is contemplated that doxepin for use in the methods described hereincan be obtained from any suitable source or made by any suitable method.As mentioned, doxepin is approved and available in higher doses (75-300milligrams) for the treatment of depression and anxiety. Doxepin HCl isavailable commercially and may be obtained in capsule form from a numberof sources. Doxepin is marketed under the commercial name SINEQUAN® andin generic form, and can be obtained in the United States generally frompharmacies in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mgdosage, and in liquid concentrate form at 10 mg/mL. Doxepin HCl can beobtained from Plantex Ltd. Chemical Industries (Hakadar Street,Industrial Zone, P.O. Box 160, Netanya 42101, Israel), Sifavitor S.p.A.(Via Livelli 1—Frazione, Mairano, Italy), or from Dipharma S.p.A. (20021Baranzate di Bollate, Milano, Italy). Also, doxepin is commerciallyavailable from PharmacyRx (NZ) (2820 1^(st) Avenue, Castlegar, B.C.,Canada) in capsule form in amounts of 10, 25, 50, 75, 100 and 150 mg.Furthermore, Doxepin HCl is available in capsule form in amounts of 10,25, 50, 75, 100 and 150 mg and in a 10 mg/ml liquid concentrate from CVSOnline Pharmacy Store (CVS.com).

Furthermore, doxepin(11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo(b,e)oxepin) can beprepared according to the method taught in U.S. Pat. No. 3,438,981,which is incorporated herein by reference in its entirety. An examplepreparation is described below in Example 1.

One available form of doxepin is a mixture of trans-(E) and cis-(Z)isomers in a ratio of approximately 85 to 15, respectively, as shownbelow. (Wyatt et al., Applied Spectroscopy. (1986) 40:369-373; which isincorporated herein by reference in its entirety). (E)-doxepin and(Z)-doxepin have the following structures:

The doxepin isomers can be prepared by any suitable method. For example,doxepin can be prepared in either of its (E) or (Z) isomers from11-[3-(Dimethylamino)propyl]-6,11-dihydrodibenzo[b,e]oxepin-11-ol astaught in U.S. Pat. No. 3,420,851, which is incorporated herein byreference in its entirety. Further, the (E) or (Z) isomers can beisolated via crystallization of doxepin hydrochloride from a mixture ofethanol and diethyl ether as taught in the incorporated material of U.S.Pat. No. 3,420,851. For example, preferably the ratio of E/Z isomers canbe about 88.3/11.7, about 89/11, about 90/10, about 94/6, about 95/5,about 99/1, about 99.5/0.5, or about 99.9/0.1. In some aspects, theratio of E/Z isomers can vary from about 86/14 to about 100/0, about88.3/11.7 to about 100/0, from about 89/11 to about 99.9/0.1, from about90/10 to about 99.5/0.5, from about 95/5 to about 99/1, from about 89/11to about 97/3, from about 89/11 to about 94.9/5.1, or the like. In someembodiments, a substantially pure or pure trans isomer can be prepared.As used herein, the trans isomer can refer to a mixture containing morethan 90%, more than 95%, more than 98%, more than 99%, more than 99.5%,more than 99.9%, or 100% of the trans isomer.

Each of the references discussed above is incorporated by reference inits entirety. In some aspects, the teachings of one or more of thereferences can be included or combined with instant methods orembodiments, while in other aspects the teachings of one or more of thereferences can be specifically excluded from the methods and embodimentsdescribed herein. As one example, the dosages used or the patientpopulation that is treated (e.g., age, health/disease profile, etc.) ina reference can be excluded or included from the methods and embodimentsdescribed herein.

Metabolites of Doxepin:

Also, isomers of doxepin metabolites can be prepared and used. By way ofillustration, some examples of metabolites of doxepin can include, butare not limited to, desmethyldoxepin, hydroxydoxepin,hydroxyl-N-desmethyldoxepin, doxepin N-oxide,N-acetyl-N-desmethyldoxepin, N-desmethyl-N-formyldoxepin, quaternaryammonium-linked glucuronide, 2-O-glucuronyldoxepin, didesmethyldoxepin,3-O-glucuronyldoxepin, or N-acetyldidesmethyldoxepin. The metabolites ofdoxepin can be obtained or made by any suitable method, including by themethods similar to those described above for doxepin.

Desmethyldoxepin has the following structure:

Desmethyldoxepin is commercially available as a forensic standard. Forexample, it can be obtained from Cambridge Isotope Laboratories, Inc.(50 Frontage Road, Andover, Mass. Desmethyldoxepin for use in themethods discussed herein can be prepared by any suitable procedure. Forexample, desmethyldoxepin can be prepared from 3-methylaminopropyltriphenylphosphonium bromide hydrobromide and6,11-dihydrodibenz(b,e)oxepin-11-one according to the method taught inU.S. Pat. No. 3,509,175, which is incorporated herein by reference inits entirety. As another example, desmethyldoxepin can be prepared inits (E) and (Z) isomers from desmethyldoxepin hydrochloride as taught inU.S. Pat. No. 5,332,661, which is incorporated herein by reference inits entirety.

Hydroxydoxepin has the following structure:

2-Hydroxydoxepin can be prepared in its (Z) and (E) isomers as taught byShu et al. (Drug Metabolism and Disposition (1990) 18:735-741), which isincorporated herein by reference in its entirety.

Hydroxyl-N-desmethyldoxepin has the following structure:

2-Hydroxy-N-desmethyldoxepin can be prepared in its (Z) and (E) isomersas described in Examples 8-9.

Doxepin N-oxide has the following structure:

Doxepin-N-oxide may be prepared by any suitable method. For example,doxepin-N-oxide can be prepared as taught by Hobbs (Biochem Pharmacol(1969) 18:1941-1954), which is hereby incorporated by reference in itsentirety.

The (Z) and (E) isomers of doxepin-N-oxide can be prepared by anysuitable method. For example, the N-oxide form of the (Z) isomer ofdoxepin can be prepared as described above for doxepin, by usingpurified (Z)-doxepin as a starting material. Likewise, N-oxide form ofthe (E) isomer of doxepin can be prepared as described above fordoxepin, by using purified (E)-doxepin as a starting material.

N-acetyl-N-desmethyldoxepin has the following structure:

The (Z) and (E) isomers of N-acetyl-N-desmethyldoxepin can be preparedby any suitable means. For example, (E)-N-acetyl-N-desmethyldoxepin hasbeen produced in filamentous fungus incubated with doxepin as taught byMoody et al. (Drug Metabolism and Disposition (1999) 27:1157-1164),hereby incorporated by reference in its entirety.

N-desmethyl-N-formyldoxepin has the following structure:

The (Z) and (E) isomers of N-desmethyl-N-formyldoxepin may be preparedby any suitable means. For example, (E)-N-desmethyl-N-formyldoxepin hasbeen produced in filamentous fungus incubated with doxepin as taught byMoody et al. (Drug Metabolism and Disposition (1999) 27:1157-1164),hereby incorporated by reference in its entirety.

N-acetyldidesmethyldoxepin has the following structure:

The (Z) and (E) isomers of N-acetyldidesmethyldoxepin may be prepared byany suitable means. For example, (E)-N-acetyldidesmethyldoxepin has beenproduced in filamentous fungus incubated with doxepin as taught by Moodyet al. (Drug Metabolism and Disposition (1999) 27:1157-1164), herebyincorporated by reference in its entirety.

Didesmethyldoxepin has the following structure:

The (Z) and (E) isomers of didesmethyldoxepin can be prepared by anysuitable means. For example, (Z)- and (E)-didesmethyldoxepin have beenisolated from plasma and cerebrospinal fluid of depressed patientstaking doxepin, as taught by Deuschle et al. (Psychopharmacology (1997)131:19-22), hereby incorporated by reference in its entirety.

3-O-glucuronyldoxepin has the following structure:

The (Z) and (E) isomers of 3-O-glucuronyldoxepin can be prepared by anysuitable means. For example, (E)-3-O-glucuronyldoxepin has been isolatedfrom the bile of rats given doxepin, as described by Shu et al. (DrugMetabolism and Disposition (1990)18:1096-1099), hereby incorporated byreference in its entirety.

2-O-glucuronyldoxepin has the following structure:

The (Z) and (E) isomers of 2-O-glucuronyldoxepin can be prepared by anysuitable means. For example, (E)-2-O-glucuronyldoxepin has been isolatedfrom the bile of rats given doxepin, and also in the urine of humansgiven doxepin, as described by Shu et al. (Drug Metabolism andDisposition (1990) 18:1096-1099), hereby incorporated by reference inits entirety.

Quaternary ammonium-linked glucuronide of doxepin (doxepinN⁺-glucuronide) has the following structure:

The (Z) and (E) isomers of doxepin N⁺-glucuronide can be obtained by anysuitable means. For example, doxepin N⁺-glucuronide can be prepared, andthe (Z) and (E) isomers thereof can be isolated as taught by Luo et al.(Drug Metabolism and Disposition, (1991) 19:722-724), herebyincorporated by reference in its entirety.

Preferably the ratio of E/Z metabolite isomers can be about 88.3/11.7,about 89/11, about 90/10, about 94/6, about 95/5, about 98/2, about99/1, about 99.5/0.5, about 99.9/0.1, or about 100/0. Most preferably,the trans isomer of the metabolite is prepared, wherein the E/Z isomericratio is greater than 90/10, greater than 95/5, greater than 98/2,greater than 99/1, greater than 99.5/0.5, greater than 99.9/0.1, or isabout 100/0. In some aspects, the ratio of E/Z isomers can vary fromabout 88.3/11.7 to about 100/0, from about 89/11 to about 99.9/0.1, fromabout 90/10 to about 99.5/0.5, from about 95/5 to about 99/1, from about89/11 to about 97/3, from about 89/11 to about 94.9/5.1, or the like.

Pharmaceutically Acceptable Salts and Prodrugs:

As mentioned above, the methods and other embodiments described hereincan utilize any suitable pharmaceutically-acceptable salt or prodrug ofdoxepin or a metabolite of doxepin. Therefore, substitution of salts andprodrugs is specifically contemplated in the various embodiments, eventhough, only doxepin or doxepin metabolites may be specificallymentioned. The pharmaceutically-acceptable salts and prodrugs can bemade by any suitable method. The acids that may be used to preparepharmaceutically acceptable acid addition salts are those that formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the acetate, benzenesulfonate, benzoate,bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate,camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride,edetate, dislyate, estolate, esylate, ethylsuccinate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate(embonate), palmitate, pantothenate, phospate/diphosphate,polygalacturonate, salicylate, stearate, subacetate, succinate, tannate,tartrate, teoclate, tosylate, triethiodode, and valerate salts.

The term “prodrug” refers to a chemical entity that is rapidlytransformed in vivo to yield an active drug, such as for example doxepinor a metabolite of doxepin, for example, by hydrolysis in blood orinside tissues. Examples of pro-drug groups can be found in, forexample, T. Higuchi and V. Stella, in “Pro-drugs as Novel DeliverySystems,” Vol. 14, A.C.S. Symposium Series, American Chemical Society(1975); H. Bundgaard, “Design of Prodrugs,” Elsevier Science, 1985; and“Bioreversible Carriers in Drug Design: Theory and Application,” editedby E. B. Roche, Pergamon Press: New York, 14-21 (1987), each of which ishereby incorporated by reference in its entirety.

Preparation and Administration of Pharmaceutical Compositions

As discussed above, the trans-(E) isomer or specified ratios of thecis-(Z) and trans-(E) isomers of doxepin, of doxepin metabolites, ofprodrugs of the same, of salts of the same, and compositions thatinclude trans-(E) isomer or specified ratios of the cis-(Z) andtrans-(E) isomers of doxepin, of a metabolite of doxepin, of a prodrugor of a doxepin salt can be used to treat a sleep disorder, for example,insomnia in a mammal, including a human. Also, doxepin isomer,metabolite isomer or isomer mix, pharmaceutically acceptable salts,and/or prodrugs of the same can be administered alone or in combinationwith other substances, such as for example, other insomnia or sleepmedications, or with other medications that treat a primary illness. Forexample, doxepin, doxepin metabolite, isomers, prodrugs or salts of thesame can be used or administered with ramelteon, VEC-162, gaboxadol,APD125, trazodone, indiplon, AVE 8488, MDL 100907, AVE 8488, MDL 100907,eszopiclone, zolpidem, tiababine, ketanserin, zaleplon or the like.Further, doxepin, doxepin metabolite, isomers, prodrugs or salts of thesame can be administered with one or more of 5-HT2 antagonists (such asketanserin), H3 agonists, orexin antagonists, noradrenergic antagonists,galanin agonists, CRH antagonists, Gaboxadol, other GABA-A directagonists, GABA reuptake inhibitors), growth hormone and growth hormoneagonists, estrogen and estrogen agonists, melatonin agonists or thelike.

The compositions as described herein can include doxepin, a doxepinisomer or isomers, a metabolite of doxepin, an isomer or isomers of ametabolite of doxepin, a pharmaceutically-acceptable salt of any of theaforementioned (alone or in combination, including with othermedications), or a prodrug of any of the aforementioned in a unit dosageform. Unit dosage form can refer to a product form in which premeasureddosages of the drug are packaged, in contrast to bulk preparations.Examples of unit dosage forms are described herein, but several nonlimiting examples, include, a pill, a tablet, a capsule, a gel cap, asmall liquid drug, an ampoule, a fast melt formulation, and the like.The isomers, salts and prodrugs alone or in combination can be includedand administered as a composition. Methods of use can include the stepof administering a therapeutically-effective amount of the compound orcomposition to a mammal in need thereof by any suitable route or methodof delivery, including those described herein.

Actual dosage levels of the compounds in the pharmaceutical compositionsmay be varied so as to administer an amount of the compound that iseffective to achieve the desired therapeutic response for a particularpatient. Examples of dosages that can be used are described more fullyelsewhere herein.

Suitable routes of administration include oral, buccal, sublingual,transdermal, rectal, topical, transmucosal, or intestinaladministration; parenteral delivery, including intramuscular,subcutaneous, intravenous, intramedullary injections, as well asintrathecal, direct intraventricular, intraperitoneal, intranasal, orintraocular injections.

For oral administration, the compounds can be formulated as pills,tablets, powders, granules, dragees, capsules, liquids, sprays, gels,syrups, slurries, suspensions and the like, in bulk or unit dosageforms, for oral ingestion by a patient to be treated. the compounds canbe formulated readily, for example, by combining the active compoundwith any suitable pharmaceutically acceptable carrier or excipient.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipients with a pharmaceutical composition as describedherein, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are listed below.Some examples include fillers such as sugars, including lactose,sucrose, mannitol, or sorbitol; cellulose preparations such as, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate.

The formulation can be in form suitable for bolus administration, forexample. Oral administration can be accomplished using fast-meltformulations, for example. As a further example, the formulations can beincluded in pre-measured ampules or syringes, push-fit capsules made ofgelatin, as well as soft, sealed capsules made of gelatin and aplasticizer, such as glycerol or sorbitol. The push-fit capsules cancontain the active ingredients in admixture with filler such as lactose,binders such as starches, and/or lubricants such as talc or magnesiumstearate and, optionally, stabilizers. In soft capsules, the activecompounds may be dissolved or suspended in suitable liquids, such asfatty oils, liquid paraffin, or liquid polyethylene glycols. Inaddition, stabilizers may be added. All formulations for oraladministration should be in dosages suitable for such administration.

For buccal administration, the compositions may take any suitable form,for example, tablets or lozenges.

For topical administration, the compounds may be formulated foradministration to the epidermis as ointments, gels, creams, pastes,salves, gels, creams or lotions, or as a transdermal patch. Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents. Lotionsmay be formulated with an aqueous or oily base and will in general alsocontaining one or more emulsifying agents, stabilizing agents,dispersing agents, suspending agents, thickening agents, or coloringagents.

For injection, the agents of the invention may be formulated in aqueoussolutions, preferably in physiologically compatible buffers such asHanks's solution, Ringer's solution, or physiological saline buffer. Fortransmucosal administration, penetrants appropriate to the barrier to bepermeated can be used in the formulation.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebulizer, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, e.g., gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly-concentrated solutions.

In addition, any of the compounds and compositions described herein canalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt. Furthermore, any of the compounds andcompositions described herein also can be formulated as a fast-meltpreparation. The compounds and compositions can also be formulated andadministered as a drip, a suppository, a salve, an ointment, anabsorbable material such a transdermal patch, or the like.

One can also administer the compounds of the invention insustained-release forms or from sustained-release drug delivery systems.A description of representative sustained release materials can be foundin the incorporated materials in Remington: The Science and Practice ofPharmacy (20^(th) ed, Lippincott Williams & Wilkens Publishers (2003)),which is incorporated herein by reference in its entirety.

A variety of techniques for formulation and administration can be foundin Remington: The Science and Practice of Pharmacy (20^(th) ed,Lippincott Williams & Wilkens Publishers (2003)), which is incorporatedherein by reference in its entirety.

As mentioned above, the compositions and formulations disclosed hereinalso can include one or more pharmaceutically-acceptable carriermaterials or excipients. Such compositions can be prepared for storageand for subsequent administration. Any acceptable carriers or diluentsfor therapeutic use can be used, including those described, for example,in the incorporated material of Remington: The Science and Practice ofPharmacy (2003). The term “carrier” material or “excipient” herein canmean any substance, not itself a therapeutic agent, used as a carrierand/or diluent and/or adjuvant, or vehicle for delivery of a therapeuticagent to a subject or added to a pharmaceutical composition to improveits handling or storage properties or to permit or facilitate formationof a dose unit of the composition into a discrete article such as acapsule or tablet suitable for oral administration. Excipients caninclude, by way of illustration and not limitation, diluents,disintegrants, binding agents, adhesives, wetting agents, polymers,lubricants, glidants, substances added to mask or counteract adisagreeable taste or odor, flavors, dyes, fragrances, and substancesadded to improve appearance of the composition. Acceptable excipientsinclude lactose, sucrose, starch powder, maize starch or derivativesthereof, cellulose esters of alkanoic acids, cellulose alkyl esters,talc, stearic acid, magnesium stearate, magnesium oxide, sodium andcalcium salts of phosphoric and sulfuric acids, gelatin, acacia gum,sodium alginate, polyvinyl-pyrrolidone, and/or polyvinyl alcohol,saline, dextrose, mannitol, lactose, lecithin, albumin, sodiumglutamate, cysteine hydrochloride, and the like. Examples of suitableexcipients for soft gelatin capsules include vegetable oils, waxes,fats, semisolid and liquid polyols. Suitable excipients for thepreparation of solutions and syrups include, without limitation, water,polyols, sucrose, invert sugar and glucose. Suitable excipients forinjectable solutions include, without limitation, water, alcohols,polyols, glycerol, and vegetable oils. The pharmaceutical compositionscan additionally include preservatives, solubilizers, stabilizers,wetting agents, emulsifiers, sweeteners, colorants, flavorings, buffers,coating agents, or antioxidants. Sterile compositions for injection canbe formulated according to conventional pharmaceutical practice asdescribed in the incorporated material in Remington: The Science andPractice of Pharmacy (2003). For example, dissolution or suspension ofthe active compound in a vehicle such as water or naturally occurringvegetable oil like sesame, peanut, or cottonseed oil or a syntheticfatty vehicle like ethyl oleate or the like may be desired. Buffers,preservatives, antioxidants and the like can be incorporated accordingto accepted pharmaceutical practice. The compound can also be made inmicroencapsulated form. In addition, if desired, the injectablepharmaceutical compositions may contain minor amounts of nontoxicauxiliary substances, such as wetting agents, pH buffering agents, andthe like. If desired, absorption enhancing preparations (for example,liposomes), can be utilized.

The compositions and formulations can include any other agents thatprovide improved transfer, delivery, tolerance, and the like. Thesecompositions and formulations can include, for example, powders, pastes,ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic)containing vesicles (such as Lipofectin™), DNA conjugates, anhydrousabsorption pastes, oil-in-water and water-in-oil emulsions, emulsionscarbowax (polyethylene glycols of various molecular weights), semi-solidgels, and semi-solid mixtures containing carbowax. Any of the foregoingmixtures may be appropriate in treatments and therapies in accordancewith the present invention, provided that at least one active ingredientin the formulation is not inactivated by the formulation and theformulation is physiologically compatible and tolerable with the routeof administration. See also Baldrick P. “Pharmaceutical excipientdevelopment: the need for preclinical guidance.” Regul. Toxicol.Pharmacol. 32(2):210-8 (2000), Charman WN “Lipids, lipophilic drugs, andoral drug delivery-some emerging concepts.” J Pharm Sci. 89(8):967 -78(2000), Powell et al. “Compendium of excipients for parenteralformulations” PDA J Pharm Sci Technol. 52:238-311 (1998) and thecitations therein for additional information related to formulations,excipients and carriers well known to pharmaceutical chemists.

Dosages

The selected dosage level can depend upon, for example, the route ofadministration, the severity of the condition being treated, and thecondition and prior medical history of the patient being treated.However, it is within the skill of the art to start doses of thecompound at levels lower than required to achieve the desiredtherapeutic effect and to gradually increase the dosage until thedesired effect is achieved. Also, a patient can be administered a higherlow dose (e.g., 6 milligrams) of the isomer or isomeric mixture, thenthe drug dosage can be tapered to a lower dosage. It will be understood,however, that the specific dose level for any particular patient candepend upon a variety of factors including the genetic makeup, bodyweight, general health, diet, time and route of administration,combination with other drugs and the severity of the particularcondition being treated.

Any suitable dosage of the trans-(E) isomer or specified ratios of thecis-(Z) and trans-(E) isomers of doxepin, a metabolite of doxepin, apharmaceutical salt, or prodrug can be used to treat the sleep disordersuch as insomnia. In some aspects, daily dosages of the trans-(E) isomeror specified ratios of the cis-(Z) and trans-(E) isomers doxepin, of adoxepin metabolite, of a pharmaceutically-acceptable salt of doxepin, orof a prodrug of doxepin may vary from about 0.001 to about 9 milligrams,about 0.001 to about 24 milligrams, about 0.001 to about 49 milligrams,about 0.001 to about 99 milligrams, about 0.001 to about 249 milligrams,about 0.001 to about 499 milligrams, about 0.01 to about 49 milligrams,about 0.01 to about 40 milligrams, from about 0.1 to about 40milligrams, about 0.01 to about 24 milligrams, about 0.01 to about 20milligrams, from about 0.5 to about 30 milligrams, about 1 to about 20milligrams, or from about 5, 10 or 20 milligrams to about 49 milligrams.Preferably, daily dosages of about 5, about 9, about 24, about 49, about99, about 249, or about 499 milligrams or less can utilized. In otheraspects, a daily dosage of greater than about 5, about 10, about 20 orabout 30 milligrams can be used. However, as it is recognized that eachindividual may react differently to a given dose of the medication used,the dosages recited should be accorded flexibility. Further, anysuitable unit dosage form can be formulated to contain the trans-(E)isomer or specified ratios of the cis-(Z) and trans-(E) isomers ofdoxepin, of a doxepin metabolite, of a prodrug of doxepin or ofpharmaceutically-acceptable salts of doxepin in the above-recitedamounts (e.g., 0.01-49 mg, or higher).

In general, lower doses of the trans-(E) isomer or specified ratios ofthe cis-(Z) and trans-(E) isomers of doxepin, of the metabolites, of thesalts or of prodrugs of the same can be preferred. These low doses aresurprisingly effective and, in most patients, have almost no sideeffects. In some embodiments, daily dosages can be about 0.01, 0.02,0.03, 0.04, 0.05, 0.06, 0.07, 0.08 or 0.09 milligrams. In someembodiments about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1.0milligrams can be used. In another embodiment, daily dosages of can beabout 0.01, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 milligrams. In anotherembodiment, daily dosages can be about 11, 12, 13, 14, 15, 16, 17, 18,19, or 20 milligrams. Therapy at each of the doses described in thisparagraph as well as ranges between these doses, are particularlycontemplated. These relatively low doses between 0.01 milligrams up to,for example, 2, 3, 4, 5, 10, 15 or 20 milligrams, have reduced sideeffects and are surprisingly effective.

Further, in some embodiments, daily dosages of the trans-(E) isomer orof specified ratios of the cis-(Z) and trans-(E) isomers of doxepin maybe up to about 25 or 30 milligrams. In another embodiment, daily dosagesof the trans-(E) isomer or of specified ratios of the cis-(Z) andtrans-(E) isomers of doxepin may be up to about 35 or 40 milligrams. Inanother embodiment, daily dosages of the trans-(E) isomer or ofspecified ratios of the cis-(Z) and trans-(E) isomers of doxepin may beup to about 45 or 49 milligrams.

Doses of the trans-(E) isomer or of the specified ratios of the cis-(Z)and trans-(E) isomers of doxepin, of doxepin metabolites, of doxepinsalts and of prodrugs of doxepin, for example, greater than 50milligrams per day can be used. For example a dosage of about 50milligrams to about 500 milligrams can be used. Also, a dosage of about50 to about 300, about 50 to about 150, or about 50 to about 75milligrams can be used, for example. Such doses can treat insomnia inpatients not suffering from depression or in otherwise healthy patients.

EXAMPLES Example 1

Doxepin is prepared by the following method.

-   -   (a) A Grignard compound is prepared in the conventional manner        from 4.8 g (0.2 gram-atom) magnesium in 100 ml ether and 30 g        (34 ml) (3-chloropropyl)-tertbutyl-ether and 16.40 grams (0.078        mol) 6,11-dihydrodibenzo-[b,e]-oxepine-11-one dissolved in 100        ml ether is added in dropwise fashion so that the contents of        the flask boil lightly. The mixture is heated for 1 hour with        agitation in a reflux condenser to complete the reaction and        then it is decomposed with ammonium chloride solution. The        product which is obtained by separating, drying and eliminating        the solvent produced, when the ether residue (24.0 g) is        extracted with ligroin, amounts to 20.3 g (80.0% of theory) of        11-(3-tertbutoxypropyl)-11-hydroxy-6,11-dihydrodibenzo-[b,e]-oxepine,        having a melting point of 124-126° C. The        (3-chloropropyl)-tertbutyl ether is thereafter obtained in the        following manner: 19 g (0.2 mol) 1-chloropropanol-(3), 50 ml        liquid isobutylene and 0.5 ml concentrated sulfuric acid are        permitted to stand for 24 hours in an autoclave, then are poured        into excess sodium bicarbonate solution and extracted with        ether. The ether solution is dried with calcium chloride and        distilled. 23.6 grams of (3-chloropropyl)-tertbutylether having        a boiling point of 150-156° C. (78% of theory) are recovered.    -   (b) 30.8 grams of the        11-(3-tertbutoxypropyl)-11-hydroxy-6,11-dihydrodibenzo-[b,e]-oxepine        obtained according to (a) above and 150 ml absolute alcoholic        hydrochloric acid are heated for 1 hour at ebullition. After        removing the solvent by evaporation, the residue is crystallized        with ligroin, 21.0 grams (88.5% of theory) of        11-(3-hydroxypropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine        having a melting point of 108-111° C. were obtained. After        recrystallization from acetic acid ester, the compound melts at        112-114° C.    -   (c) 5.0 ml thionyl chloride dissolved in 5 ml benzene is added        dropwise at room temperature to 12.6 g (0.05 mol) of the        11-(3-hydroxypropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine        obtained in part (b) above. After 1 hour of standing, the        contents of the flask are heated at ebullition for 2 hours. The        volatile components are thereafter removed and the remainder        distilled using high vacuum. The yield amounts to 10.6 g (78.5%        of theory) of        11-(3-chloropropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine        having a B.P.0.1 169-172° C., a melting point of 106-111° C.        After recrystallization from 20 ml of acetic acid ester, 9.1 g        (67.5% of theory) of pure product having a melting point of        113-115° C. is obtained. The crude product can however be used        quite easily for further processing.    -   (d) 5.4 g (0.02 mol) of the        11-(3-chloropropylidene)-6,11-dihydrodibenzo-[b,e]-oxepine,        prepared according to (c) above, in 20 ml tetrahydrofuran and        5.5 g (0.12 mol) dimethylamine in 20 ml ethanol is heated        together for 3 hours using a glass autoclave and a temperature        of 95-100° C. (boiling water bath). Water and 6 N hydrochloric        acid are added to the contents of the autoclave and the mixture        is extracted with ether. The separated, aqueous-acid components        are then made alkaline with dilute caustic soda solution, and        the oil thereby separated is taken up in ether. The ether        residue, after distillation in a high vacuum, produces 4.1 g        (73.5% of theory) of        11-(3-dimethylamino-propylidene)-6,11-dihydrodibenzo-[b,e]-oxepine,        having a B.P._(0.1) 147-150° C. The melting point of the        hydrochloride is 182-184° C. (recrystallized from isopropanol).

Example 2 Preparation of Doxepin Isomer

Five grams of the cis/trans mixture of doxepin hydrochloride isconverted to the free base and then to the maleate salt, M.P. 168-169°C. Several recrystallizations from ethanol afford a pure isomericmaleate, M.P. 172-173° C. This is reconverted to the free base and thento the hydrochloric acid-addition salt. This is purified byrecyrstallization from a mixture of ethanol and ether; M.P. 192-193° C.The other pure isomer is isolated by the concentration of thecrystallization liquors to dryness, followed by converting the residueto the free base and then converting the base to the hydrochloric-acidaddition salt. After re-crystallization from a mixture of ethanol andether, the salt has a M.P. of 209-210.5° C.

Example 3 Preparation of Desmethyldoxepin

Desmethyldoxepin is prepared according to the following method.Anhydrous 3-methylaminopropyltriphenylphosphonium bromide hydrobromide(1530 g) prepared as in U.S. Pat. No. 3,509,175, is suspended in 4.5 ldry tetrahydrofuran and 6.0 moles of butyl lithium in heptane is addedduring 1 hour. After an additional 30 minutes, 483 g of6,11-dihydrodibenz(b,e)oxepin-11-one, is added to the deep red solutionand the reaction is maintained at reflux for 10 hours. Water, 500 ml, isadded at room temperature and the solvent is removed in vacuo. The cruderesidue is treated with 10% hydrochloric acid until acidic (pH 2) andthen 1.5 l benzene is added. After stirring, the mixture separates intothree phases (an insoluble hydrochloride salt product phase, an aqueousphase and an organic phase). The benzene layer is removed by decantationand the remaining mixture is rendered basic with 10% sodium hydroxidesolution and is extracted with 3×1500 ml portions of benzene. Thebenzene extracts are washed, then dried with anhydrous sodium sulfateand concentrated in a vacuum leaving a solid residue ofdesmethyldoxepin.

Example 4 Preparation of (e)-desmethyldoxepin

(E)-Desmethyldoxepin is prepared from doxepin hydrochloride as follows.Doxepin hydrochloride (E/Z=85/15) (55.0 g, 0.174 mol) is dissolved in600 mL H₂O, made basic with 6M NaOH, and extracted with CHCl₃ (3×600mL). The CHCl₃ extracts are combined, dried over Na₂SO₄, and solventremoved in vacuo. The resulting oil is dissolved in 250 mL EtOH, then21.15 g (0.182 mol) of maleic acid dissolved in 100 mL EtOH is addedslowly, with stirring, followed by an additional 350 mL EtOH. Theresulting cloudy solution is refluxed until it becomes clear, thenallowed to stand overnight at room temperature; the resulting crystalsare isolated by vacuum filtration. Additional recrystallization fromEtOH yields a white crystalline product ((E)-Doxepin maleate) with anE/Z ratio of 98/2. (E)-Doxepin maleate (2.50 g, 6.32 mmol) is thenpartially dissolved in 60 mL H2O, made basic with 6 M NaOH, andextracted with CHCl3 (3×60 mL). The CHCl3 extracts are combined, washedwith 60 mL brine, dried over Na2SO4, and solvent removed in vacuo. Theresulting oil is re-dissolved in 10 mL CHCl3, 1.8 mL (13 mmol) oftriethylamine added, 1.8 mL (13 mmol) of2,2,2-trichloroethylchloro-formate added, and reaction stirred under N2for 3.5 hours. The completed reaction is then diluted with 140 mL Et2O,washed successively with 0.5M HCl (2×140 mL), H₂O (140 mL), and brine(140 mL), then dried over MgSO4 and solvent removed in vacuo. Resultingmaterial is further purified by silica gel column chromatography,eluting with EtOAc/Hex (20/80), to afford 1.48 g (3.36 mmol) of thedesired product as a clear oil. The N-protected (E)-desmethyldoxepinintermediate (1.44 g, 3.27 mmol) is then dissolved in 12 mL THF, 2.88 gof zinc powder added, 2.3 mL of 1M sodium phosphate (pH=5.5) added, andreaction stirred for 17 hours. The reaction mixture is then vacuumfiltered, filtrate solvent removed in vacuo, and resulting residuepurified by silica gel column chromatography, eluting withTHF/MeOH/NH₄OH (85/15/0.4), then THF/MeOH/NH₄OH (75/25/0.4), to afford744 mg (2.80 mmol) of the desired product as a pale yellow solid.

Example 5 Preparation of (z)-desmethyl doxepin

(Z)-Desmethyldoxepin is prepared from doxepin hydrochloride as follows.Doxepin hydrochloride (E/Z=85/15) (100 g, 0.317 mol) is dissolved in 800mL H₂O, made basic with 6M NaOH, and extracted with CHCl₃ (3×800 mL).The CHCl₃ extracts are combined, dried over Na₂SO₄, and solvent removedin vacuo. The resulting oil is dissolved in 700 mL EtOH, then 36.7 g(0.317 mol) of maleic acid dissolved in 600 mL EtOH is added slowly,with stirring. The resulting cloudy solution is refluxed until clear,then allowed to stand overnight at room temperature. Crystals areisolated by vacuum filtration and the mother liquor saved. Crystals arerecrystallized two additional times as above, and the three motherliquors saved and combined and solvent removed in vacuo.Recrystallization of mother liquor material from refluxing EtOHeventually affords 24 g of a mother liquor product which is 65% Z isomerin composition. Recrystallization of this material from 450 mL EtOHgives crystals (9.1 g) which are 80% Z isomer. This material isrecrystallized from 170 mL CHCl₃/CCl₄ (50/50) at 4° C., yielding 7.65 gof crystalline material which is 87% Z isomer in composition. Threeadditional recrystallizations from CHCl₃/CCl₄ eventually affords 5.12 g(12.9 mmol) of the desired product ((Z)-Doxepin maleate) with an E/Zratio of 4/96; melting point: 162°-163° C. (Z)-Doxepin maleate (1.00 g,2.53 mmol) is then partially dissolved in 35 mL H₂O, made basic with 6 MNaOH, and extracted with CHCl₃ (3×35 mL). The CHCl₃ extracts arecombined, washed with 35 mL brine, dried over Na₂SO₄, and solventremoved in vacuo. The resulting oil is re-dissolved in 4 mL CHCl₃, 0.65mL (4.7 mmol) of triethylamine added, 0.65 mL (4.7 mmol) of2,2,2-trichloroethyl-chloroformate added, and reaction stirred under N₂for 3.5 hours. The completed reaction is then diluted with 50 mL Et₂O,washed successively with 0.5 M HCl (2×50 mL), H₂O (50 mL), and brine (50mL), then dried over MgSO₄ and solvent removed in vacuo. Resultingmaterial is further purified by silica gel column chromatography,eluting with EtOAc/Hex (20/80), to afford 710 mg (1.61 mmol) of thedesired product as a clear oil. The N-protected (Z)-desmethyldoxepin(679 mg, 1.54 mmol) is then dissolved in 5.7 mL THF, 1.36 g of zincpowder added, 1.1 mL of 1 M sodium phosphate (pH=5.5) added, andreaction stirred for 17 hours. The reaction mixture is then vacuumfiltered, filtrate solvent removed in vacuo, and resulting residuepurified by silica gel column chromatography, eluting withTHF/MeOH/NH₄OH (85/15/0.4), then THF/MeOH/NH₄OH (82/18/0.4), to afford364 mg (1.37 mmol) of the desired product as a pale yellow solid.

Example 6 Preparation of(Z)-2-Hydroxy-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin

A mixture of2-methoxy-11-(3-dimethylaminopropyl)-6,11-dihydrodibenzo[b,e]oxepin (165mg, 0.005 mol) with glacial acetic acid (0.2 ml) and hydriodic acid (0.2ml, 57%) was stirred and heated for 5 hr at 90° C. The product was thenextracted and purified by pouring into ice water (25 ml), made alkalinewith sodium hydroxide (2N) and extracted with ether (2×10 ml). Theaqueous layer was then adjusted to pH 6.8 with hydrochloric acid (6 N).The mixture was then brought to pH 7 by the addition of sodiumbicarbonate solution (5%) and extracted with chloroform (2×10 ml). Theextract was dried over anhydrous sodium sulfate and evaporated in vacuoto give a yellowish solid. The crude reaction product was purified bypreparative TLC (chloroform/toluene/methanol/ammonia, 4:3:2:1, v/v).

Example 7 Preparation of(E)-2-Hydroxy-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin

A mixture of(Z)-2-Hydroxy-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin (2.5 mg, 8.5×10⁻⁶ mol) was dissolved in a mixture ofhydrochloric acid (1 ml) and methanol (9 ml) and heated at 140° C. (oilbath) for 4 hr. The product was isolated by means of HPLC andevaporation of solvents.

Example 8 Preparation of(Z)-2-Hydroxy-11-(3-methylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin

A mixture of2-methoxy-11-(3-methylaminopropyl)-6,11-dihydrodibenzo[b,e]oxepin (0.005mol) with glacial acetic acid (0.2 ml) and hydriodic acid (0.2 ml, 57%)istirred and heated for 5 hr at 90° C. The product is then extracted andpurified by pouring into ice water (25 ml), made alkaline with sodiumhydroxide (2N) and extracted with ether (2×10 ml). The aqueous layer isthen adjusted to pH 6.8 with hydrochloric acid (6N). The mixture is thenbrought to pH 7 by the addition of sodium bicarbonate solution (5%) andextracted with chloroform (2×10 ml). The extract is dried over anhydroussodium sulfate and evaporated in vacuo to give a yellowish solid. Thecrude reaction product is purified by preparative TLC(chloroform/toluene/methanol/ammonia, 4:3:2:1, v/v).

Example 9 Preparation of(E)-2-Hydroxy-11-(3-methylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin

A mixture of(Z)-2-Hydroxy-11-(3-methylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin(2.5 mg) is dissolved in a mixture of hydrochloric acid (1 ml) andmethanol (9 ml) and heated at 140° C. (oil bath) for 4 hr. The productis isolated by means of HPLC and evaporation of solvents.

Example 10 Preparation of doxepin-N-oxide

An aqueous solution of doxepin hydrochloride was made alkaline andextracted with methylene chloride. Solvent was removed and the residue,dissolved in methanol, was treated for 5 days with an excess of 30%hydrogen peroxide. Chromatographic examination indicated that thedoxepin had been completely replaced by a more polar substancedetermined from its mass spectrum to be the N-oxide.

Hobbs, D. C., Distribution and Metabolism of Doxepin (1969) BiochemPharmacol 18:1941-1954; which is incorporated herein by reference in itsentirety.

Example 11 Preparation of (Z) doxepin-N-oxide

An aqueous solution of purified (Z)-doxepin hydrochloride is madealkaline and extracted with methylene chloride. Solvent is removed andthe residue, dissolved in methanol, is treated for 5 days with an excessof 30% hydrogen peroxide. Chromatographic examination indicates that thedoxepin has been completely replaced by a more polar substancedetermined from its mass spectrum to be the N-oxide of the (Z) isomer ofdoxepin.

Example 12 Preparation of (E) doxepin-N-oxide

An aqueous solution of purified (E)-doxepin hydrochloride is madealkaline and extracted with methylene chloride. Solvent is removed andthe residue, dissolved in methanol, is treated for 5 days with an excessof 30% hydrogen peroxide. Chromatographic examination indicates that thedoxepin has been completely replaced by a more polar substancedetermined from its mass spectrum to be the N-oxide of the (E) isomer ofdoxepin.

Example 13 Isolation of (E)-N-acetyl-N-desmethyldoxepin,(E)-N-desmethyl-N-formyldoxepin, and (E)-N-acetyldidesmethyldoxepin

(E)-N-acetyl-N-desmethyldoxepin, (E)-N-desmethyl-N-formyldoxepin, and(E)-N-acetyldidesmethyldoxepin are isolated from Cunninghamella elegans(C.elegans) as described in the incorporated materials of Moody et al.(Drug Metabolism and Disposition (1999) 27:1157-1164). Briefly, culturesof C. elegans ATCC 9245 are incubated for 48 h at 26° C. on a rotaryshaker operating at 125 rpm and then 10 mg of doxepin hydrochloride(E./Z ratio 83:16%) dissolved in 0.5 ml sterile physiological salinesolution are added. After 96 h of incubation, the contents of eachflask, are filtered through glass wool into a separatory funnel andextracted with three equal volumes of ethyl acetate. The organicextracts are dried over sodium sulfate and evaporated to dryness invacuo at 34° . The residue is dissolved in methanol and concentrated toapproximately 100 μL by evaporation for analysis by HPLC.

The extract is injected repeatedly into a semipreparative scale HPLCsystem consisting of a Beckman model 100A pump, a Waters 486 turntableUV absorbance detector, and a Shimadzu model CR601 Chromatopacintegrator. The compounds are eluted using a linear gradient of 30 to75% methanol-buffer (v/v) over 30 min at 1.0 ml/min with a 10.0×250 mmcolumn. The buffer used is 25 mM ammonium acetate, pH 7.2. Compoundswith similar retention times are pooled. NMR and mass spectral analysisconfirms the isolation of (E)-N-acetyl-N-desmethyldoxepin,(E)-N-desmethyl-N-formyldoxepin, and (E)-N-acetyldidesmethyldoxepin.

Example 14 Isolation of (Z)-N-acetyl-N-desmethyldoxepin,(Z)-N-desmethyl-N-formyldoxepin, and (Z)-N-acetyldidesmethyldoxepin

(Z)-N-acetyl-N-desmethyldoxepin, (Z)-N-desmethyl-N-formyldoxepin, and(Z)-N-acetyldidesmethyldoxepin are isolated from Cunninghamella elegans(C.elegans) as described above in Example 12 for the (E) isomers.However, unlike Example 13, the cultures are initially incubated withdoxepin enriched for the cis (Z)-isomer of doxepin at a Z/E ratio ofgreater than 85:15. NMR and mass spectral analysis confirms theisolation of (Z)-N-acetyl-N-desmethyldoxepin,(Z)-N-desmethyl-N-formyldoxepin, and (Z)-N-acetyldidesmethyldoxepin.

Example 15 Isolation of (E)-and (Z)-N-didesmethyldoxepin

(E)-and (Z)-N-didesmethyldoxepin are isolated from blood serum andcerebrospinal fluid of patients treated with doxepin according to themethods described in the incorporated materials of Deuschle et al.(Psychopharmacology (1997) 131:19-22). Briefly, blood and cerebrospinalfluid are collected from patients being treated with doxepin. Aftercentrifugation, (15000 g for 5 min), 100 μl of the samples is injecteddirectly onto a clean-up column (10.0×4.0 mm) filled with LichrospherRP-8 DIOL. Interfering plasma or CSF constituents are washed to wasteusing water containing 5% acetonitrile at a flow rate of 1.5 ml/min.After 5 min the flow is switched onto an analytical column and the drugsof interest are separated using methanol: acetonitrile: 0.008M phosphatebuffer, pH 6.4 (188:578:235; V/V) for elution. NMR and mass spectralanalysis confirms the isolation of (E)-N-didesmethyldoxepin and(Z)-N-didesmethyldoxepin.

Example 16 Isolation of (E)-2-O-glucuronyldoxepin and(E)-3-O-glucuronyldoxepin

(E)-2-O-glucuronyldoxepin and (E)-3-O-glucuronyldoxepin are isolatedfrom rat bile according to the methods described in the incorporatedmaterials of Shu et al. (Drug Metabolism and Disposition(1990)18:1096-1099). Briefly, samples of rat bile are collected fromrats for 4 hours after intraperitoneal injection with doxepinhydrochloride (28 mg/kg). The samples are chromatographed on a gradientHPLC system that consists of two solvent delivery pumps (Waters M045), asystem controller (Waters Model 720), a UV absorbance detector (WatersModel 441), and an integrator (Hewlett 3390A). Chromotography is carriedout on a column packed with Spherisorb nitrile (3 μm, 0.46×15 cm) andmaintained at 50° C. The analysis begins with an initial isocraticperiod (1 min) with 95% solvent A (water) and 5% solvent B(acetonitrile/methanol, 75:25, v/v). Thereafter, a linear gradientelution is established by increasing the proportion of solvent B from 5%to 100% from 1 to 16 min, followed by a final period (4 min) ofisocratic elution with 100% solvent B. The flow rate is 1.5 ml/min andUV absorbance is monitored at 254 nm with a sensitivity of 0.005 AUFS.NMR and mass spectral analysis confirms the isolation of(E)-2-O-glucuronyldoxepin and (E)-3-O-glucuronyldoxepin.

Example 17 Isolation of (Z)-2-O-glucuronyldoxepin and(Z)-3-O-glucuronyldoxepin

(Z)-2-O-glucuronyldoxepin and (Z)-3-O-glucuronyldoxepin are isolatedfrom rat bile according to the methods described above in Example 16with the exception that the rats are injected with doxepin enriched forthe cis (Z)-isomer of doxepin at a Z/E ratio of greater than 85:15. NMRand mass spectral analysis confirms the isolation of(Z)-2-O-glucuronyldoxepin and (Z)-3-O-glucuronyldoxepin.

Example 18 Preparation of (E)-and (Z)-doxepin N⁺-glucuronide

The quaternary ammonium-linked glucuronide of doxepin (doxepinN⁺-glucuronide) is obtained by organic synthesis as described in theincorporated materials of Luo et al. (Drug Metabolism and Disposition,(1991) 19:722-724). Briefly, the synthetic procedure involvesquaternization of commercial samples of doxepin withmethyl(2,3,4-tri-O-acetyl-1-bromo-1-deoxy-α-D-glucopyranosid)urinate,and subsequent removal of the protecting groups by treatment with sodiumhydroxide. Thus, to prepare the (Z)-isomer of doxepin N⁺-glucuronide,(Z)-doxepin is used as the starting material. To prepare the (E)-isomerof doxepin, (E)-doxepin is used as the starting material.

Example 19

The patient suffers from transient or short-term insomnia. At the timeof consultation, he is otherwise healthy with normal affect with nodepression, anxiety or substance overuse. He is prescribed a mixture ofcis-(Z) and trans-(E) isomers of doxepin or a doxepin metabolitecontaining greater than 88.2% trans-(E) isomer in a daily dosage of0.0001 milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6milligrams, 10 milligrams, 20 milligrams or 40 milligrams, taken priorto bedtime. Follow up reveals that the administration of the specifiedisomeric mixture of doxepin relieves the insomnia and has him sleepingwell.

Example 20

The patient suffers from transient or short-term insomnia. At the timeof consultation, he is otherwise healthy with normal affect with nodepression, anxiety or substance overuse. He is prescribed a mixture ofcis-(Z) and trans-(E) isomers of doxepin or a doxepin metabolitecontaining greater than 90% trans-(E) isomer in a daily dosage of 0.0001milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6 milligrams, 10milligrams, 20 milligrams or 40 milligrams, taken prior to bedtime.Follow up reveals that the administration of the specified isomericmixture of doxepin relieves the insomnia and has him sleeping well.

Example 21

The patient suffers from transient or short-term insomnia. At the timeof consultation, he is otherwise healthy with normal affect with nodepression, anxiety or substance overuse. He is prescribed a mixture ofcis-(Z) and trans-(E) isomers of doxepin or a doxepin metabolitecontaining greater than 90% and less than 99.5% trans-(E) isomer in adaily dosage of 0.0001 milligram, 0.1 milligram, 1 milligram, 3milligrams, 6 milligrams, 10 milligrams, 20 milligrams or 40 milligrams,taken prior to bedtime. Follow up reveals that the administration of thespecified isomeric mixture of doxepin relieves the insomnia and has himsleeping well.

Example 22

The patient suffers from transient or short-term insomnia. At the timeof consultation, he is otherwise healthy with normal affect with nodepression, anxiety or substance overuse. He is prescribed the trans-(E)isomer of doxepin or a doxepin metabolite in a daily dosage of 0.0001milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6 milligrams, 10milligrams, 20 milligrams or 40 milligrams, taken prior to bedtime.Follow up reveals that the administration of the doxepin isomer relievesthe insomnia and has him sleeping well.

Example 23

The patient suffers from transient or short-term insomnia. At the timeof consultation, she also suffers from depression. She is prescribed amixture of cis-(Z) and trans-(E) isomers of doxepin or a doxepinmetabolite containing greater than 88.2% trans-(E) isomer in a dailydosage of 0.0001 milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6milligrams, 10 milligrams, 20 milligrams or 40 milligrams, taken priorto bedtime. Follow up reveals that the administration of the specifiedisomeric mixture of doxepin relieves the insomnia and has her sleepingwell.

Example 24

The patient suffers from transient or short-term insomnia. At the timeof consultation, she also suffers from depression. She is prescribed amixture of cis-(Z) and trans-(E) isomers of doxepin or a doxepinmetabolite containing greater than 90% trans-(E) isomer in a dailydosage of 0.0001 milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6milligrams, 10 milligrams, 20 milligrams or 40 milligrams, taken priorto bedtime. Follow up reveals that the administration of the specifiedisomeric mixture of doxepin relieves the insomnia and has her sleepingwell.

Example 25

The patient suffers from transient or short-term insomnia. At the timeof consultation, she also suffers from depression. She is prescribed amixture of cis-(Z) and trans-(E) isomers of doxepin or a doxepinmetabolite containing greater than 90% and less than 99.5% trans-(E)isomer in a daily dosage of 0.0001 milligram, 0.1 milligram, 1milligram, 3 milligrams, 6 milligrams, 10 milligrams, 20 milligrams or40 milligrams, taken prior to bedtime. Follow up reveals that theadministration of the specified isomeric mixture of doxepin relieves theinsomnia and has her sleeping well.

Example 26

The patient suffers from transient or short-term insomnia. At the timeof consultation, she also suffers from depression. She is prescribed thetrans-(E) isomer of doxepin or a doxepin metabolite in a daily dosage of0.0001 milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6milligrams, 10 milligrams, 20 milligrams or 40 milligrams, taken priorto bedtime. Follow up reveals that the administration of the doxepinisomer relieves the insomnia and has her sleeping well.

Example 27

The patient suffers from chronic insomnia. At the time of consultation,he is otherwise healthy with normal affect with no depression, anxietyor substance abuse. He is prescribed a mixture of cis-(Z) and trans-(E)isomers of doxepin or a doxepin metabolite containing greater than 88.2%trans-(E) isomer in a daily dosage of 0.0001 milligram, 0.1 milligram, 1milligram, 3 milligrams, 6 milligrams, 10 milligrams, 20 milligrams or40 milligrams, taken prior to bedtime. Follow up reveals that theadministration of the specified isomeric mixture of doxepin relieves theinsomnia and has him sleeping well.

Example 28

The patient suffers from chronic insomnia. At the time of consultation,he is otherwise healthy with normal affect with no depression, anxietyor substance abuse. He is prescribed a mixture of cis-(Z) and trans-(E)isomers of doxepin or a doxepin metabolite containing greater than 90%trans-(E) isomer in a daily dosage of 0.0001 milligram, 0.1 milligram, 1milligram, 3 milligrams, 6 milligrams, 10 milligrams, 20 milligrams or40 milligrams, taken prior to bedtime. Follow up reveals that theadministration of the specified isomeric mixture of doxepin relieves theinsomnia and has him sleeping well.

Example 29

The patient suffers from chronic insomnia. At the time of consultation,he is otherwise healthy with normal affect with no depression, anxietyor substance abuse. He is prescribed a mixture of cis-(Z) and trans-(E)isomers of doxepin or a doxepin metabolite containing greater than 90%and less than 99.5% trans-(E) isomer in a daily dosage of 0.0001milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6 milligrams, 10milligrams, 20 milligrams or 40 milligrams, taken prior to bedtime.Follow up reveals that the administration of the specified isomericmixture of doxepin relieves the insomnia and has him sleeping well.

Example 30

The patient suffers from chronic insomnia. At the time of consultation,he is otherwise healthy with normal affect with no depression, anxietyor substance abuse. He is prescribed the trans-(E) isomer of doxepin ora doxepin metabolite in a daily dosage of 0.0001 milligram, 0.1milligram, 1 milligram, 3 milligrams, 6 milligrams, 10 milligrams, 20milligrams or 40 milligrams, taken prior to bedtime. Follow up revealsthat the administration of the doxepin isomer relieves the insomnia andhas him sleeping well.

Example 31

The patient suffers from chronic insomnia. At the time of consultation,she also suffers from depression. She is prescribed a mixture of cis-(Z)and trans-(E) isomers of doxepin or a doxepin metabolite containinggreater than 88.2% trans-(E) isomer in a daily dosage of 0.0001milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6 milligrams, 10milligrams, 20 milligrams or 40 milligrams, taken prior to bedtime.Follow up reveals that the administration of the specified isomericmixture of doxepin relieves the insomnia and has her sleeping well.

Example 32

The patient suffers from chronic insomnia. At the time of consultation,she also suffers from depression. She is prescribed a mixture of cis-(Z)and trans-(E) isomers of doxepin or a doxepin metabolite containinggreater than 90% trans-(E) isomer in a daily dosage of 0.0001 milligram,0.1 milligram, 1 milligram, 3 milligrams, 6 milligrams, 10 milligrams,20 milligrams or 40 milligrams, taken prior to bedtime. Follow upreveals that the administration of the specified isomeric mixture ofdoxepin relieves the insomnia and has her sleeping well.

Example 33

The patient suffers from chronic insomnia. At the time of consultation,she also suffers from depression. She is prescribed a mixture of cis-(Z)and trans-(E) isomers of doxepin or a doxepin metabolite containinggreater than 90% and less than 99.5% trans-(E) isomer in a daily dosageof 0.0001 milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6milligrams, 10 milligrams, 20 milligrams or 40 milligrams, taken priorto bedtime. Follow up reveals that the administration of the specifiedisomeric mixture of doxepin relieves the insomnia and has her sleepingwell.

Example 34

The patient suffers from chronic insomnia. At the time of consultation,she also suffers from depression. She is prescribed the trans-(E) isomerof doxepin or a doxepin metabolite in a daily dosage of 0.0001milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6 milligrams, 10milligrams, 20 milligrams or 40 milligrams, taken prior to bedtime.Follow up reveals that the administration of the doxepin isomer relievesthe insomnia and has her sleeping well.

Example 35

The patient suffers from maintenance (non-chronic) insomnia. At the timeof consultation, he is otherwise healthy with normal affect with nodepression, anxiety or substance overuse. He is prescribed a mixture ofcis-(Z) and trans-(E) isomers of doxepin or a doxepin metabolitecontaining greater than 88.2% trans-(E) isomer in a daily dosage of0.0001 milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6milligrams, 10 milligrams, 20 milligrams or 40 milligrams, taken priorto bedtime. Follow up reveals that the administration of the specifiedisomeric mixture of doxepin relieves the insomnia and has him sleepingwell.

Example 36

The patient suffers from maintenance (non-chronic) insomnia. At the timeof consultation, he is otherwise healthy with normal affect with nodepression, anxiety or substance overuse. He is prescribed a mixture ofcis-(Z) and trans-(E) isomers of doxepin or a doxepin metabolitecontaining greater than 90% trans-(E) isomer in a daily dosage of 0.0001milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6 milligrams, 10milligrams, 20 milligrams or 40 milligrams, taken prior to bedtime.Follow up reveals that the administration of the specified isomericmixture of doxepin relieves the insomnia and has him sleeping well.

Example 37

The patient suffers from maintenance (non-chronic) insomnia. At the timeof consultation, he is otherwise healthy with normal affect with nodepression, anxiety or substance abuse. He is prescribed a mixture ofcis-(Z) and trans-(E) isomers of doxepin or a doxepin metabolitecontaining greater than 90% and less than 99.5% trans-(E) isomer in adaily dosage of 0.0001 milligram, 0.1 milligram, 1 milligram, 3milligrams, 6 milligrams, 10 milligrams, 20 milligrams or 40 milligrams,taken prior to bedtime. Follow up reveals that the administration of thespecified isomeric mixture of doxepin relieves the insomnia and has himsleeping well.

Example 38

The patient suffers from maintenance (non-chronic) insomnia. At the timeof consultation, he is otherwise healthy with normal affect with nodepression, anxiety or substance overuse. He is prescribed the trans-(E)isomer of doxepin or a doxepin metabolite in a daily dosage of 0.0001milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6 milligrams, 10milligrams, 20 milligrams or 40 milligrams, taken prior to bedtime.Follow up reveals that the administration of the doxepin isomer relievesthe insomnia and has him sleeping well.

Example 39

The patient suffers from maintenance (chronic) insomnia. At the time ofconsultation, he is otherwise healthy with normal affect with nodepression, anxiety or substance abuse. He is prescribed a mixture ofcis-(Z) and trans-(E) isomers of doxepin or a doxepin metabolitecontaining greater than 88.2% trans-(E) isomer in a daily dosage of0.0001 milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6milligrams, 10 milligrams, 20 milligrams or 40 milligrams, taken priorto bedtime. Follow up reveals that the administration of the specifiedisomeric mixture of doxepin relieves the insomnia and has him sleepingwell.

Example 40

The patient suffers from maintenance (chronic) insomnia. At the time ofconsultation, he is otherwise healthy with normal affect with nodepression, anxiety or substance abuse. He is prescribed a mixture ofcis-(Z) and trans-(E) isomers of doxepin or a doxepin metabolitecontaining greater than 90% trans-(E) isomer in a daily dosage of 0.0001milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6 milligrams, 10milligrams, 20 milligrams or 40 milligrams, taken prior to bedtime.Follow up reveals that the administration of the specified isomericmixture of doxepin relieves the insomnia and has him sleeping well.

Example 41

The patient suffers from maintenance (chronic) insomnia. At the time ofconsultation, he is otherwise healthy with normal affect with nodepression, anxiety or substance abuse. He is prescribed a mixture ofcis-(Z) and trans-(E) isomers of doxepin or a doxepin metabolitecontaining greater than 90% and less than 99.5% trans-(E) isomer in adaily dosage of 0.0001 milligram, 0.1 milligram, 1 milligram, 3milligrams, 6 milligrams, 10 milligrams, 20 milligrams or 40 milligrams,taken prior to bedtime. Follow up reveals that the administration of thespecified isomeric mixture of doxepin relieves the insomnia and has himsleeping well.

Example 42

The patient suffers from maintenance (chronic) insomnia. At the time ofconsultation, he is otherwise healthy with normal affect with nodepression, anxiety or substance abuse. He is prescribed the trans-(E)isomer of doxepin or a doxepin metabolite in a daily dosage of 0.0001milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6 milligrams, 10milligrams, 20 milligrams or 40 milligrams, taken prior to bedtime.Follow up reveals that the administration of the doxepin isomer relievesthe insomnia and has him sleeping well.

Example 43

The patient suffers from onset (non-chronic) insomnia. At the time ofconsultation, she is otherwise healthy with normal affect with nodepression, anxiety or substance abuse. She is prescribed a mixture ofcis-(Z) and trans-(E) isomers of doxepin or a doxepin metabolitecontaining greater than 88.2% trans-(E) isomer in a daily dosage of0.0001 milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6milligrams, 10 milligrams, 20 milligrams or 40 milligrams, taken priorto bedtime. Follow up reveals that the administration of the specifiedisomeric mixture of doxepin relieves the insomnia and has her sleepingwell.

Example 44

The patient suffers from onset (non-chronic) insomnia. At the time ofconsultation, she is otherwise healthy with normal affect with nodepression, anxiety or substance abuse. She is prescribed a mixture ofcis-(Z) and trans-(E) isomers of doxepin or a doxepin metabolitecontaining greater than 90% trans-(E) isomer in a daily dosage of 0.0001milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6 milligrams, 10milligrams, 20 milligrams or 40 milligrams, taken prior to bedtime.Follow up reveals that the administration of the specified isomericmixture of doxepin relieves the insomnia and has her sleeping well.

Example 45

The patient suffers from onset (non-chronic) insomnia. At the time ofconsultation, she is otherwise healthy with normal affect with nodepression, anxiety or substance abuse. She is prescribed a mixture ofcis-(Z) and trans-(E) isomers of doxepin or a doxepin metabolitecontaining greater than 90% and less than 99.5% trans-(E) isomer in adaily dosage of 0.0001 milligram, 0.1 milligram, 1 milligram, 3milligrams, 6 milligrams, 10 milligrams, 20 milligrams or 40 milligrams,taken prior to bedtime. Follow up reveals that the administration of thespecified isomeric mixture of doxepin relieves the insomnia and has hersleeping well.

Example 46

The patient suffers from onset (non-chronic) insomnia. At the time ofconsultation, she is otherwise healthy with normal affect with nodepression, anxiety or substance abuse. She is prescribed the trans-(E)isomer of doxepin or a doxepin metabolite in a daily dosage of 0.0001milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6 milligrams, 10milligrams, 20 milligrams or 40 milligrams, taken prior to bedtime.Follow up reveals that the administration of the doxepin isomer relievesthe insomnia and has her sleeping well.

Example 47

The patient suffers from onset (chronic) insomnia. At the time ofconsultation, she is otherwise healthy with normal affect with nodepression, anxiety or substance abuse. She is prescribed a mixture ofcis-(Z) and trans-(E) isomers of doxepin or a doxepin metabolitecontaining greater than 88.2% trans-(E) isomer in a daily dosage of0.0001 milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6milligrams, 10 milligrams, 20 milligrams or 40 milligrams, taken priorto bedtime. Follow up reveals that the administration of the specifiedisomeric mixture of doxepin relieves the insomnia and has her sleepingwell.

Example 48

The patient suffers from onset (chronic) insomnia. At the time ofconsultation, she is otherwise healthy with normal affect with nodepression, anxiety or substance abuse. She is prescribed a mixture ofcis-(Z) and trans-(E) isomers of doxepin or a doxepin metabolitecontaining greater than 90% trans-(E) isomer in a daily dosage of 0.0001milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6 milligrams, 10milligrams, 20 milligrams or 40 milligrams, taken prior to bedtime.Follow up reveals that the administration of the specified isomericmixture of doxepin relieves the insomnia and has her sleeping well.

Example 49

The patient suffers from onset (chronic) insomnia. At the time ofconsultation, she is otherwise healthy with normal affect with nodepression, anxiety or substance abuse. She is prescribed a mixture ofcis-(Z) and trans-(E) isomers of doxepin or a doxepin metabolitecontaining greater than 90% and less than 99.5% trans-(E) isomer in adaily dosage of 0.0001 milligram, 0.1 milligram, 1 milligram, 3milligrams, 6 milligrams, 10 milligrams, 20 milligrams or 40 milligrams,taken prior to bedtime. Follow up reveals that the administration of thespecified isomeric mixture of doxepin relieves the insomnia and has hersleeping well.

Example 50

The patient suffers from onset (chronic) insomnia. At the time ofconsultation, she is otherwise healthy with normal affect with nodepression, anxiety or substance abuse. She is prescribed the trans-(E)isomer of doxepin or a doxepin metabolite in a daily dosage of 0.0001milligram, 0.1 milligram, 1 milligram, 3 milligrams, 6 milligrams, 10milligrams, 20 milligrams or 40 milligrams, taken prior to bedtime.Follow up reveals that the administration of the doxepin isomer relievesthe insomnia and has her sleeping well.

Example 51

The patient suffers from a sleep disorder. The patient is prescribed amixture of cis-(Z) and trans-(E) isomers of apharmaceutically-acceptable salt of doxepin or a doxepin metabolitecontaining greater than 88.2% trans-(E) isomer in a daily dosage of0.0001 milligram, 0.1 milligram, 1 milligram, 2 milligrams, 3milligrams, 6 milligrams, 10 milligrams, 20 milligrams or 40 milligrams,taken prior to bedtime. Follow up reveals that the administration of thespecified isomeric mixture of the doxepin salt relieves the insomnia andhas him sleeping well.

Example 52

The patient suffers from a sleep disorder. The patient is prescribed amixture of cis-(Z) and trans-(E) isomers of apharmaceutically-acceptable salt of doxepin or a doxepin metabolitecontaining greater than 90% trans-(E) isomer in a daily dosage of 0.0001milligram, 0.1 milligram, 1 milligram, 2 milligrams, 3 milligrams, 6milligrams, 10 milligrams, 20 milligrams or 40 milligrams, taken priorto bedtime. Follow up reveals that the administration of the specifiedisomeric mixture of the doxepin salt relieves the insomnia and has himsleeping well.

Example 53

The patient suffers from a sleep disorder. The patient is prescribed amixture of cis-(Z) and trans-(E) isomers of apharmaceutically-acceptable salt of doxepin or a doxepin metabolitecontaining greater than 90% and less than 99.5% trans-(E) isomer in adaily dosage of 0.0001 milligram, 0.1 milligram, 1 milligram, 2milligrams, 3 milligrams, 5 milligrams, 6 milligrams, 10 milligrams, 20milligrams or 40 milligrams, taken prior to bedtime. Follow up revealsthat the administration of the specified isomeric mixture of the doxepinsalt relieves the insomnia and has him sleeping well.

Example 54

The patient suffers from a sleep disorder. The patient is prescribed thetrans-(E) isomer of a pharmaceutically-acceptable salt of doxepin or adoxepin metabolite in a daily dosage of 0.0001 milligram, 0.1 milligram,1 milligram, 2 milligrams, 3 milligrams, 5 milligrams, 6 milligrams, 10milligrams, 20 milligrams or 40 milligrams, taken prior to bedtime.Follow up reveals that the administration of the isomer of the doxepinsalt relieves the insomnia and has him sleeping well.

Example 55

The patient suffers from a sleep disorder. The patient is prescribed amixture of cis-(Z) and trans-(E) isomers of a prodrug of doxepin or adoxepin metabolite containing greater than 88.2% trans-(E) isomer in adaily dosage of 0.0001 milligram, 0.1 milligram, 1 milligram, 2milligrams, 3 milligrams, 5 milligrams, 6 milligrams, 10 milligrams, 20milligrams or 40 milligrams, taken prior to bedtime. Follow up revealsthat the administration of the specified isomeric mixture of the doxepinprodrug relieves the insomnia and has him sleeping well.

Example 56

The patient suffers from a sleep disorder. The patient is prescribed amixture of cis-(Z) and trans-(E) isomers of a prodrug salt of doxepin ora doxepin metabolite containing greater than 90% trans-(E) isomer in adaily dosage of 0.0001 milligram, 0.1 milligram, 1 milligram, 2milligrams, 3 milligrams, 5 milligrams, 6 milligrams, 10 milligrams, 20milligrams or 40 milligrams, taken prior to bedtime. Follow up revealsthat the administration of the specified isomeric mixture of the doxepinprodrug relieves the insomnia and has him sleeping well.

Example 57

The patient suffers from a sleep disorder. The patient is prescribed amixture of cis-(Z) and trans-(E) isomers of a prodrug of doxepin or adoxepin metabolite containing greater than 90% and less than 99.5%trans-(E) isomer in a daily dosage of 0.0001 milligram, 0.1 milligram, 1milligram, 2 milligrams, 3 milligrams, 5 milligrams, 6 milligrams, 10milligrams, 20 milligrams or 40 milligrams, taken prior to bedtime.Follow up reveals that the administration of the specified isomericmixture of the doxepin prodrug relieves the insomnia and has himsleeping well.

Example 58

The patient suffers from a sleep disorder. The patient is prescribed thetrans-(E) isomer of a prodrug of doxepin or a doxepin metabolite in adaily dosage of 0.0001 milligram, 0.1 milligram, 1 milligram, 2milligrams, 3 milligrams, 5 milligrams, 6 milligrams, 10 milligrams, 20milligrams or 40 milligrams, taken prior to bedtime. Follow up revealsthat the administration of the isomer of the doxepin prodrug relievesthe insomnia and has him sleeping well.

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only.

What is claimed is:
 1. A method for treating insomnia characterized bydifficulties with sleep maintenance, the method comprising:administering a dosage of doxepin or a pharmaceutically acceptable saltthereof to a patient having a sleep disorder in which, for a given 8hour period of desired sleep, the patient experiences fragmented sleepduring the final 60 minutes of said period, wherein the dosage ofdoxepin is between about 1 and about 6 mg, wherein the doxepin or saltthereof is a geometric isomer mixture containing about 88.3% to about100.0% of the trans-(E) isomer or is 100% trans-(E) isomer, and whereinthe dosage is administered prior to the start of the sleep period. 2.The method of claim 1, wherein said geometric isomer mixture containsmore than 90% of the trans-(E) isomer.
 3. The method of claim 1, whereinsaid geometric isomer mixture contains more than 95% of the trans-(E)isomer.
 4. The method of claim 1, wherein said geometric isomer mixturecontains more than 98% of the trans-(E) isomer.
 5. The method of claim1, wherein said geometric isomer mixture contains more than 99% of thetrans-(E) isomer.
 6. The method of claim 1, wherein said geometricisomer mixture contains at least 99.5% or 99.9% of the trans-(E) isomer.7. The method of claim 1, wherein the dosage is effective to improve theinsomnia while minimizing next day residual sedation.
 8. The method ofclaim 1, wherein the dosage is about 1 milligram.
 9. The method of claim1, wherein the dosage is about 3 milligrams.
 10. The method of claim 1,wherein the dosage is about 6 milligrams.
 11. A method for treatinginsomnia characterized by difficulties with sleep maintenance, themethod comprising: administering a dosage of doxepin or apharmaceutically acceptable salt thereof to a patient having a sleepdisorder in which, for a given 8 hour period of desired sleep, thepatient experiences early awakenings during the final 60 minutes of saidperiod, wherein the dosage of doxepin is between about 1 and about 6 mg,wherein the doxepin or salt thereof is a geometric isomer mixturecontaining about 88.3% to about 100.0% of the trans-(E) isomer or is100% trans-(E) isomer, and wherein the dosage is administered prior tothe start of the sleep period.
 12. The method of claim 11, wherein saidgeometric isomer mixture contains more than 90% of the trans-(E) isomer.13. The method of claim 11, wherein said geometric isomer mixturecontains more than 95% of the trans-(E) isomer.
 14. The method of claim11, wherein said geometric isomer mixture contains more than 98% of thetrans-(E) isomer.
 15. The method of claim 11, wherein said geometricisomer mixture contains more than 99% of the trans-(E) isomer.
 16. Themethod of claim 11, wherein said geometric isomer mixture contains atleast 99.5% or 99.9% of the trans-(E) isomer.
 17. The method of claim11, wherein the dosage is effective to improve the insomnia whileminimizing next day residual sedation.
 18. The method of claim 11,wherein the dosage is about 1 milligram.
 19. The method of claim 11,wherein the dosage is about 3 milligrams.
 20. The method of claim 11,wherein the dosage is about 6 milligrams.